The intestinal microbiota, a complex ecosystem of microorganisms, has emerged as an important player in modulating various aspects of human health and disease. The microbiota is in a state of constant cross talk with itself and its host, and these interactions regulate several aspects of host homeostasis, including immune responses. Studies have demonstrated a relationship between the microbiota and outcomes of several cancer immunotherapies. This review explores the different roles of intestinal microbiota in shaping the efficacy and safety of cancer immunotherapies, including allogeneic hematopoietic cell transplantation, immune checkpoint blockade, and CAR T cell therapy.

In this review, we explore the current landscape of preclinical and clinical therapeutics targeting epigenetic complexes in cancer, focusing on targets with enzymatic inhibitors, degraders, or ligands capable of disrupting protein–protein interactions. Current strategies face challenges such as limited single-agent clinical efficacy due to insufficient disruption of chromatin complexes and incomplete dissociation from chromatin. Further complications arise from the adaptability of cancer cell chromatin and, in some cases, dose-limiting toxicity. The advent of targeted protein degradation (TPD) through degrader compounds such as proteolysis-targeting chimeras provides a promising approach. These innovative molecules exploit the endogenous ubiquitin–proteasome system to catalytically degrade target proteins and disrupt complexes, potentially amplifying the efficacy of existing epigenetic binders. We highlight the status of TPD-harnessing moieties in clinical and preclinical development, as these compounds may prove crucial for unlocking the potential of epigenetic complex modulation in cancer therapeutics.

Recent therapeutic advances have significantly improved the outcome for patients with multiple myeloma (MM). The backbone of successful standard therapy is the combination of Ikaros degraders, glucocorticoids, and proteasome inhibitors that interfere with the integrity of myeloma-specific superenhancers by directly or indirectly targeting enhancer-bound transcription factors and coactivators that control expression of MM dependency genes. T cell engagers and chimeric antigen receptor T cells redirect patients’ own T cells onto defined tumor antigens to kill MM cells. They have induced complete remissions even in end-stage patients. Unfortunately, responses to both conventional therapy and immunotherapy are not durable, and tumor heterogeneity, antigen loss, and lack of T cell fitness lead to therapy resistance and relapse. Novel approaches are under development to target myeloma-specific vulnerabilities, as is the design of multimodality immunological approaches, including and beyond T cells, that simultaneously recognize multiple epitopes to prevent antigen escape and tumor relapse.

Dysregulated transcription factor activity is a defining feature of various cancer types. As such, targeting oncogenic transcriptional dependency has long been pursued as a potential therapeutic approach. However, transcription factors have historically been deemed as undruggable targets due to their highly disordered structures and lack of well-defined binding pockets. Nevertheless, interest in their pharmacologic inhibition and destruction has not dwindled in recent years. Here, we discuss new small-molecule-based approaches to target various transcription factors. Ligands with different mechanisms of action, such as inhibitors, molecular glue degraders, and proteolysis targeting chimeras, have recently seen success preclinically and clinically. We review how these strategies overcome the challenges presented by targeting transcription factors.

Digital pathology, powered by whole-slide imaging technology, has the potential to transform the landscape of cancer research and diagnosis. By converting traditional histopathological specimens into high-resolution digital images, it paves the way for computer-aided analysis, uncovering a new horizon for the integration of artificial intelligence (AI) and machine learning (ML). The accuracy of AI- and ML-driven tools in distinguishing benign from malignant tumors and predicting patient outcomes has ushered in an era of unprecedented opportunities in cancer care. However, this promising field also presents substantial challenges, such as data security, ethical considerations, and the need for standardization. In this review, we delve into the needs that digital pathology addresses in cancer research, the opportunities it presents, its inherent potential, and the challenges it faces. The goal of this review is to stimulate a comprehensive discourse on harnessing digital pathology and AI in health care, with an emphasis on cancer diagnosis and research.

The direct targeting of chromatin-associated proteins is increasingly recognized as a potential therapeutic strategy for the treatment of cancer. In this review, we discuss a prominent example, namely, small-molecule inhibitors that target the menin–KMT2A interaction. These molecules are currently being investigated in clinical trials and showing significant promise. We describe the unique specificity of menin–KMT2A protein complexes for the transcriptional regulation of a small subset of genes that drive developmental and leukemic gene expression. We review the chromatin-associated KMT2A complex and the protein–protein interaction between menin and KMT2A that is essential for the maintenance of different types of cancer cells, but most notably acute myeloid leukemia (AML). We also summarize the development of menin inhibitors and their effects on chromatin. Finally, we discuss the promising early results from clinical trials in patients with AML and the recent discovery of therapy-resistant menin mutants that validate menin as a therapeutic target but also may present therapeutic challenges.

Pediatric brain tumors comprise a diverse set of diseases. (Epi)genomic analyses have provided insights into the biology of these tumors, stratifying them into distinct subtypes with different oncogenic driver mechanisms and developmental origins. A feature shared by these tumors is their initiation within neural stem or progenitor cells that undergo stalled differentiation in unique, niche-dependent ways. In this review, we provide an overview of how (epi)genomic characterization has revealed pediatric brain tumor origins and underlying biology. We focus on the best characterized tumor types—gliomas, ependymomas, medulloblastomas—as well as select rarer types such as embryonal tumors with multilayered rosettes, atypical teratoid/rhabdoid tumors, and choroid plexus carcinomas in which new insights have been made. The discovery of diverse developmental origins of these tumors and their defining molecular characteristics has led to a better understanding of their etiologies, with important implications for diagnostics, future therapy development, and clinical trial design.

Autologous chimeric antigen receptor (CAR) T cell therapy, produced from the patient's own T cells, has changed the treatment landscape for hematologic malignancies but has some drawbacks that prevent large-scale clinical application, including logistical complexities in supply, patient T cell health, treatment delays, and limited manufacturing slots. Allogeneic, or off-the-shelf, CAR T cell therapies have the potential to overcome many of the limitations of autologous therapies, with the aim of bringing benefit to all patients eligible for treatment. This review highlights the progress and challenges of allogeneic cell therapies for cancer and the various approaches that are being evaluated preclinically and in clinical trials to enhance the persistence and antitumor efficacy of allogeneic CAR T cells, including new strategies to avoid immune rejection.

Regeneration and cancer share genetic mechanisms and cellular processes. While highly regenerative cells are often the source of cancer, persistent injury or imperfect regeneration in the form of wound healing can lead to degenerative conditions that favor cancer development. Thus, the causal interplay between regeneration and cancer is complex. This article focuses on understanding how functional variation in regeneration and wound healing might influence the risk of cancer. Variation in regenerative capacity might create trade-offs or adaptations that significantly alter cancer risk. From this perspective, we probe the causal relationships between regeneration, wound healing, and cancer.